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Enhanced autophagy in cytarabine arabinoside-resistant U937 leukemia cells and its potential as a target for overcoming resistance

Authors
 JUNE-WON CHEONG  ;  YUNDEOK KIM  ;  JU IN EOM  ;  HOI-KYUNG JEUNG  ;  YOO HONG MIN 
Citation
 Molecular Medicine Reports, Vol.13(4) : 3433-3440, 2016 
Journal Title
 Molecular Medicine Reports 
ISSN
 1791-2997 
Issue Date
2016
MeSH
Antimetabolites, Antineoplastic/pharmacology ; Autophagy/drug effects* ; Blotting, Western ; Cytarabine/pharmacology* ; Drug Resistance, Neoplasm/drug effects ; Genes, Reporter ; Green Fluorescent Proteins/genetics ; Humans ; Hydroxychloroquine/toxicity ; Leukemia, Myeloid, Acute/metabolism ; Leukemia, Myeloid, Acute/pathology ; Microscopy, Electron, Transmission ; Microscopy, Fluorescence ; Microtubule-Associated Proteins/metabolism ; U937 Cells
Keywords
autophagy ; Ara-C-resistant ; U937 ; acute myeloid leukemia ; treatment
Abstract
Autophagy is a lysosomal degradation mechanism that is essential for cell survival, differentiation, development, and homeostasis. Autophagy protects cells from various stresses, including protecting normal cells from harmful metabolic conditions, and cancer cells from chemotherapeutics. In the current study, a cytarabine arabinoside (Ara‑C)‑sensitive U937 leukemia cell line and an Ara‑C‑resistant U937 (U937/AR) cell line were assessed for baseline autophagy activity by investigating the LC3‑I conversion to LC3‑II, performing EGFP‑LC3 puncta, an acidic autophagolysosome assay, and measuring the expression of various autophagy‑related genes. The results demonstrated significantly higher autophagic activity in the U937/AR cells compared with the U937 cells, when the cells were cultured with or without serum. Furthermore, an increase in the autophagic activity in starved U937/AR cells was demonstrated, compared with that in the starved U937 cells. Administration of an autophagy inhibitor demonstrated no change in cell death in the two cell lines when cultured with serum, however, it induced cell death regardless of the Ara‑C sensitivity when the cell lines were cultured without serum. In addition, the U937 cells demonstrated an Ara‑C resistance when cultured without serum. Co‑treatment with Ara‑C and the autophagy inhibitor significantly induced cell death in the U937/AR and Ara‑C‑sensitive U937 cells. In conclusion, autophagy serves an important role in protecting U937 cells from Ara‑C and in the development of Ara‑C resistance. Inhibition of autophagy combined with the Ara‑C treatment in the U937 cells augmented the anti‑leukemic effect of Ara‑C and overcame Ara‑C resistance, suggesting that autophagy may be an important therapeutic target to further improve the treatment outcome in patients with acute myeloid leukemia.
Files in This Item:
T201601174.pdf Download
DOI
10.3892/mmr.2016.4949
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
김윤덕(Kim, Yun Deok) ORCID logo https://orcid.org/0000-0002-5336-7936
민유홍(Min, Yoo Hong) ORCID logo https://orcid.org/0000-0001-8542-9583
정준원(Cheong, June-Won) ORCID logo https://orcid.org/0000-0002-1744-0921
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/146726
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